The long-term objective of this proposal is to develop a lead-212/bismuth-212 (Pb-212/bi-212) generator and sufficient amounts of source material that will support clinical trials and approved drug products. The use of alpha emitting radionuclides in pre-clinical studies is yielding promising results. Treatments for metastatic melanoma, ovarian cancer and disseminated intraperitoneal cancers are being investigated and are proceeding to clinical trials. There is no effective treatment for these diseases, which take more than 20,000 lives a year in the US. For this promising research to continue, an isotope generator that is approved for human use and a steady supply of this isotope in quantities required to support clinical trials and approved drug products is required. The current isotope generator design was developed for use in small-scale pre-clinical research and is not suited for routine use in a clinical or radiopharmaceutical environment. It is an organic resin based cation exchange column typically eluted with dilute hydrochloric acid. Organic resins are susceptible to radiolytic damage; especially from high energy/high LET alpha emissions. The acid etuate is not directly compatible with antibody or peptide labeling conditions, and it is corrosive to needles, other metallic components and septa with metallic fillers. The latter can introduce impurities that compete with the radionuclides in labeling reactions. In addition, the precursor isotopes that are used to produce this isotope generator were derived from legacy material developed during the Cold War years. This amount of this material is limited and is not sufficient to support later phase trials or approved drug products. The specific aims of this proposal is to (1) design and demonstrate a Pb-212 isotope generator that is suitable for administering to humans and for use in a clinical environment and (2) determine the optimal path to increase the amount of starting material necessary to support the production of Pb-212 generators in sufficient quantities anticipated by clinical trials and approved drug products.